PHARMACEUTICALS
1. NAME 1.1 SubstanceTetanus antitoxin for human use 1.2 GroupImmunologic agent 1.3 SynonymsImmunoserum Tetanicum Tetanus antitoxin (BP)Tetanus immune globulin 1.4 Identification numbers 1.4.1 CAS number
1.4.2 Other numbers
1.5 Brand names, Trade namesTetanus Antitoxin (USA)
Tetabulin (Swiss)
Tetavenine (Swiss) 1.6 Manufacturers, ImportersImmunoloski Zavad (Yugoslavia)2. SUMMARY 2.1 Main risks and target organsAcute exposure to tetanus antitoxin occurs when the product is
used to provide temporary passive immunity. The main risks
are adverse effects due to intolerance, such as hypotamia,
flushing of face, oppressive sensation. Target organs of
tetanus vaccine are the skin, central nervous system (CNS),
and cardiovascular system. Anaphylactic shock may occur, but
more rarely than serum sickness, hypotension, urticaria, and
skin eruptions. Adverse reactions are more common when the
antitoxin is prepared from the serum of animals. If the
antitoxin used is prepared from a pool of human plasma,
adverse reactions are less frequent and less significant than
those which may occur when toxin of animal origin is used. 2.2 Summary of clinical effectsAnaphylactic shock and serum sickness. Hypotension, flushing
of the face, dizziness, urticaria, and skin eruptions. 2.3 DiagnosisIs based on history of antitoxin administration and occurrence
of intolerance, characterized in general by flushing of the
face, sensation of oppression, hypotenia. In case of severe
intolerance, anaphylactic shock, dizziness, hypotension, cough,
wheezing, dyspepsia and glottic oedema may occur. 2.4 First aid measures and management principlesTherapy for anaphylactic shock: Administer 1 mg adrenaline
(1ml of a 1:1000 solution) or 300 to 500 microg noradrenaline
(0.3 to 0.5 ml of a 1:1000 solution) by intramuscular (IM)
injection. This dose should be repeated every half an hour
until blood pressure is normalized. Oral antihistamines and
intravenous corticosteroids (5 to 100 mg of prednisone IV)
should be given at the same time. Antihistamines should be
continued for 10 days after the onset of anaphylactic shock.
Therapy for serum sickness: calcium preparations IV and
antihistamines per oral route.3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substanceTetanus antitoxin may be obtained from the serum or plasma of
healthy horses immunized against tetanus toxin or, more
commonly, from pooled human plasma. The latter is a
lyophilized concentrate which contains immunoglobulins G with
a minimum of 100 IU/ml of antitetanus antibodies. Only
selected human plasma is used (HIV and HBs negative).
Tetanus antitoxin may also be a refined and concentrated
protein, chiefly globulin, containing antitoxin antibodies
obtained from the serum or plasma of healthy horses that have
been immunized against tetanus toxin or toxoid (USP). It
contains not less than 400 units per ml (Reynolds, 1990). 3.2 Chemical structureGlobulin proteins (of human or animal origin). 3.3 Physical properties 3.3.1 Properties of the substance
Tetanus antitoxin occurs as a transparent or
slightly opalescent liquid, brownish, yellowish
or greenish in colour. It is practically
odourless or may have an odour due to the
preservative. 3.3.2 Properties of the locally available formulation
Immunoglobulins are dissolved in physiological saline
solution and 30 to 50 mmol/L phenol or 30 mmol/l
tricresol is added as preservative. 3.4 Other characteristics 3.4.1 Shelf-life of the substance
Tetanus antitoxin should be used within 1 or 2 years
when the manufacturer's cold storage was 5 or 0°C
respectively. Human antitoxin should be kept between +2
°C and 8°C 3.4.2 Shelf-life of the locally available formulation
Same as section 3.4.1. 3.4.3 Storage conditions
Tetanus antitoxin should be refrigerated at 2-9°C and
should not be frozen. 3.4.4 Bioavailability
Not relevant 3.4.5 Specific properties and composition
Tetanus antitoxin contains chlorocresol and glycerol as
preservative and stabilizer, respectively. Human
antitoxin preparation consists of 90% gammaglobulins
plus glycine (22.5 mg/ml), sodium chloride (3 mg/ml) and
thiomersal (0.1 mg/ml).4. USES 4.1 IndicationsTetanus antitoxin neutralizes the toxin produced by
Clostridium tetani; the toxin has high affinity for new
cells and antitoxin is unlikely to have an effect on
toxin that is no longer circulating. Tetanus antitoxins
have been used to provide temporary passive immunity
against tetanus but tetanus immunoglobulins are
preferred (Reynolds, 1990; McEvoy et al. 1988). Human
globulin offers the advantage of greater protection, a
lower risk of adverse effects and requires only one-
tenth of the dosage compared to antitoxin of animal
origin. 4.2 Therapeutic dosage 4.2.1 Adults
For prophylaxis after injury, non-immune or partially
immune persons may be given 3,000 to 5,000 units of
tetanus antitoxin subcutaneously or intramuscularly
(Reynolds, 1990).
For adults below 30 kg the dosage is 1,500 units. 4.2.2 Children
The dose for children of less than 30 kg body weight is
usually 1,500 units (Reynolds, 1990). For children over
30 kg in weight the dosage is usually 3,000-5,000 units
(McEvoy et al. 1988). Doses of 50,000 to 100,000 units
have been given in the treatment of established tetanus;
part of this dose is administered by intravenous
injection with the remainder being given
intramuscularly. Treatment with tetanus antitoxin
should be initiated as soon as possible; the wound
should be treated surgically to remove foreign material
and exposed to air.
Note: Sensitivity testing and desensitization: [Prior
to use of tetanus antitoxin, an intradermal skin test or
a conjunctival test for serum sensitivity should be
performed. Adrenaline (epinephrine) should be available
during sensitivity testing for immediate treatment of
hypersensitivity reactions if they occur] 4.3 ContraindicationsSensitivity testing (e.g., skin test, conjunctival test)
should be conducted in all individuals, regardless of clinical
history, prior to administration of tetanus antitoxin.5. ROUTES OF ENTRY 5.1 OralNot relevant 5.2 InhalationNot relevant 5.3 DermalDuring sensitivity testing and desensitization. 5.4 EyeDuring sensitivity testing and desensitization. 5.5 ParenteralMost frequent route of exposure: intramuscular, subcutaneous
or intravenous. Intrathecal therapy for tetanus has been
carried out with antitetanus immuneglobulin (Abrutyn and
Berlin, 1991). 5.6 OtherNo data available6. KINETICS 6.1 Absorption by route of exposureNo data available. 6.2 Distribution by route of exposureNo data available. 6.3 Biological half-life by route of exposureHuman toxin has a long half-life: approximately 21 days 6.4 MetabolismNo data available. 6.5 Elimination by route of exposureNo data available.7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics
No data available. 7.1.2 Pharmacodynamics
No data available. 7.2 Toxicity 7.2.1 Human data
7.2.1.1 Adults
7.2.1.2 Children
7.2.2 Relevant animal data
A case of acute hypatic failure in a horse being treated
for tetanus was attributed to tetanus antitoxin of
equine origin (Step et al, 1991). 7.2.3 Relevant in vitro data
No data available. 7.3 CarcinogenicityNo data available. 7.4 TeratogenicityControlled studies have not been done in animals; however,
problems in humans have been documented (FDA Pregnancy
Category C USP DI 1990). Immune pregnant women confer
protection on their infants via placental transmission of
maternal antibody. Pregnant women who are inadequately
immunized or unimmunized and who may deliver their infants
under unhygienic conditions may expose their infants to
neonatal tetanus. For inadequately immunized or unimmunized
pregnant women, it is recommended that immunization with
tetanus antitoxin be initiated or continued during the last
two trimesters. Unimmunized women should receive the first two
doses of the primary series before childbirth (USP DI 1990). 7.5 MutagenicityNo data available. 7.6 InteractionsMedications containing immunosuppressants or radiation therapy
should not be administered concomitantly with tetanus toxoid
(USP DI 1990). In such cases normal defence mechanisms are
suppressed and the patient's antibody response to tetanus
toxoid may be decreased. This precaution does not apply to
adrenocorticosteroids used as short-term replacement therapy
(less than 2 weeks), as systemic therapy, or by other routes
of administration that do not cause immunosuppression.
Where possible, immunosuppressive therapy should be
interrupted when immunization is required because of a tetanus-
prone wound (USP DI 1990). 7.7 Main adverse effectsHypersensitivity reactions are liable to occur after the
injection of any serum of animal origin, i.e., serum sickness,
anaphylaxis, hypotension, urticaria and shock.
Serum sickness may develop up to several weeks following
administration of tetanus antitoxin and is characterized by:
urticaria, malaise, lymphadenopathy, arthralgia, and fever,
vomiting diarrhoea, bronchospasm. There may also be nephritis,
myocarditis, polyarthritis, neuritis and ureitis (Reynolds,
1990; McEvoy, 1988).
Minor reactions include: skin eruptions, local pain, numbness
and occasional joint pains which may appear up to several days
following administration of tetanus antitoxin. However, these
reactions appear to be brief in duration and insignificant.
Local pain or local erythema and urticaria may occur without
systemic effects 7-10 days following administration of tetanus
antitoxin and may last for about 2 days (McEvoy, 1988).8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation 8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations 8.6 References9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion
Not relevant 9.1.2 Inhalation
Not relevant 9.1.3 Skin exposure
No data available. 9.1.4 Eye contact
No data available. 9.1.5 Parenteral exposure
No data available. 9.1.6 Other
No data available. 9.2 Chronic poisoning 9.2.1 Ingestion
No data available. 9.2.2 Inhalation
No data available. 9.2.3 Skin exposure
No data available. 9.2.4 Eye contact
No data available. 9.2.5 Parenteral exposure
No data available. 9.2.6 Other
No data available. 9.3 Course, prognosis, cause of deathAdverse reactions to antitoxin of human origin are not
frequent. They consist of transient tenderness and
inflammation at the site of injection and other local
reactions. Allergic reactions are rare and usually self-
limited. Tetanus antitoxin prepared from the serum of animals
may induce anaphylaxis, with hypotension, dyspnoea, orticaria
and shock. Serum sickness may occur 7 to 10 days after
injection, with fever, vomiting, diarrhoea, bronchospasm and
urticaria (rarely, nephritis and myocarditis, polyarthritis,
neuritis and uveitis may be observed) (Reynolds, 1990). 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular
Tachycardia may be seen in case of intolerance to be
toxin. 9.4.2 Respiratory
Neuritis may result from severe serum sickness. 9.4.3 Neurological
9.4.3.1 CNS
No data available. 9.4.3.2 Peripheral nervous system
Neuritis may result from severe serum sickness. 9.4.3.3 Autonomic nervous system
No data available 9.4.3.4 Skeletal and smooth muscle
No data available 9.4.4 Gastrointestinal
No data available 9.4.5 Hepatic
No data available 9.4.6 Urinary
9.4.6.1 Renal
No data available 9.4.6.2 Other
No data available 9.4.7 Endocrine and reproductive systems
No data available 9.4.8 Dermatological
Skin eruptions, local pain, local erythema and urticaria
may occur. 9.4.9 Eye, ear, nose, throat: local effects
Glottic oedema may occur in case of anaphylaxis 9.4.10 Haematological
No data available. 9.4.11 Immunological
Nephritis, myocarditis, polyarthritis, neuritis and
uveitis may occur after serum sickness. 9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No data available. 9.4.12.2 Fluid and electrolyte disturbances
No data available. 9.4.12.3 Others
No data available. 9.4.13 Allergic reactions
The risk of hypersensitivity reactions, (anaphylaxis,
serum sickness) remains significant for several weeks
following administration of tetanus antitoxin (see also
7.7). 9.4.14 Other clinical effects
No data available 9.4.15 Special risks
Pregnancy: human antitoxin may be used during
pregnancy.
Breastfeeding: problems in humans have not been
documented.
Enzyme deficiencies: no data available. 9.5 OtherNo data available. 9.6 Summary10. MANAGEMENT 10.1 General principlesManagement principles consist of control of anaphylactic
shock, serum sickness and hypotension.
In case of intolerance to the antitoxin its administration
should be stopped immediately.
Antihistamines, corticosteroids and sympathomimetics may
have to be used to counteract the adverse reaction. 10.2 Relevant laboratory analyses 10.2.1 Sample collection
No data available 10.2.2 Biomedical analysis
No data available 10.2.3 Toxicological analysis
No data available 10.2.4 Other investigations
No data available 10.3 Life supportive procedures and symptomatic/specific
treatmentIn case of anaphylaxis, epinephrine (1:10.000) should be
administered intravenously. An antihistamine may be
indicated for mild allergic reactions. For anaphylactic
reactions, adrenaline (epinephrine) with maintenance of
vital functions is necessary.
Adult dosage: If anaphylaxis occurs, give 0.2 to 0.5 mg of
adrenaline intramuscularly or subcutaneously; the dose
should be repeated every 10 to 15 min as needed and if
necessary increased up to a maximum of 1 mg per dose. If
analphylactic shock occurs, give 0.5 mg of adrenaline
intramuscularly or subcutaneously, followed by a slow
intravenous adminstration of adrenaline or 0.0025 to 0.005
mg. The dose may be repeated every 5 to 15 min as required.
Children's dosage: If anaphylaxis occurs, give adrenaline
0.01 mg/kg body weight or 0.3 mg per square metre of body
surface, up to a maximum of 0.5 mg per dose, by subcutaneous
injection; repeat every 15 minutes for two doses, then every
four hours as needed. If anaphylactic shock occurs, give
0.3 mg adrenaline intramuscularly or intravenously; repeat
every 15 minutes for three or four doses, if necessary. 10.4 DecontaminationNot relevant. 10.5 EliminationNot relevant. 10.6 Antidote treatment 10.6.1 Adults
No antidote available. 10.6.2 Children
No antidote available. 10.7 Management discussionNo data available.11. ILLUSTRATIVE CASES 11.1 Case reports from literatureA severe and irreversible case of perceptive deafness was
reported following the administration of antitoxin for
tetanus prophylaxis (Pantazoupoulos, 1966, reported in
Martindale, 1982). A rare case of bilateral perceptive
deafness following clinical tetanus was reported in a 15 day-
old neonate treated with tetanus antitoxin (human gamma
globulins) and penicillin. Although the mechanism of
auditory nerve damage was not clear, the authors attributed
it to the tetanus toxin and not to the antitoxin (Skevas et
al., 1991). 11.2 Internally extracted data on casesNo data available. 11.3 Internal casesTo be completed by the poisons centre.12. Additional information 12.1 Availability of antidotesNot relevant. 12.2 Specific preventive measuresNo data available. 12.3 OtherRare cases of agammaglobulinemia may have secondary
reactions to antitoxin of human origin.13. REFERENCESAbrutyn E, Berlin JA (1991). Lutrathecal therapy in tetanus,
meta-analysis. JAMA Oct 23-30; 266 (16): 2262-7.
Briggs GG, Freeman RK, Yaffe SJ (1986). Tetanus/diphtheria
toxoids (adult). Drugs in pregnancy and lactation. A reference
guide to foetal and neonatal risk. Second Edition. Williams &
Wilkins, Baltimore, 423/t.
McEvoy GK et al (1988). Serums, Toxoids and Vaccines Tetanus
antitoxin. American Hospital Formulary Service Drug Information
88. American Society of the Hospital Pharmacists, Montgomery
Avenue, Bethesda, (1871-1969).
Reynolds JEF, ed. (1990) Martindale, the Extra Pharmacopoeia,
30th Edition. Pharmaceutical Press, London.
Skevas A, Kastanioudakis I, Exarchakos G, Assimakopoulos D,
(1992); Perceptive bilateral deafness collowing clinical tetanus
to a neanate. Int J. Pediatr-Otorhinolaryngol. Mar; 23(2); 177-
80.
Step DL, Blue JT, Dill SG (1991). Penicillin-induced hemolytic
anaemia and acute hepatic failure following treatment of tetanus
in a horse. Cornell Vet. Jan 1981 (1): 13-8.
The United States Pharmacological Convention Inc., (1990).
Tetanus toxoid. USP Drug Information for Health Care
Professionals. Vol. I. 1580-2583.
Zink GL (1990). Immunizing agents and diagnostic antigens. In:
Osol Arthur, Remington's Pharmaceutical Sciences, 16th Edition,
Mack Publishing Company, Easton, Pennsylvania, 1324-1340.14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)Authors: Dr O.J. Kasilo
Drug and Toxicology Information Service, (DaTIS),
Department of Pharmacy
University of Zimbabwe Medical School
P.O.Box A178
Avondale
Harare
Zimbabwe
Dr C.F.B. Nbachi
Department of Clinical Pharmacology and Toxicology
University of Zimbabwe Medical School
P.O.Box A178
Avondale
Harare
Zimbabwe
Tel: 263-4-790233/791631 Ext. 117/172
Fax: 263-4-303 292
Telex: 265801 UNIV ZW.
Date: April 1990
Peer review: Strasbourg, France, April 1990
Review: IPCS, May 1994